Identifying genes regulating platelet reactivity

描述（由申请方提供）：冠状动脉、脑动脉和外周动脉中的血小板血栓是全球发病率和死亡率的最常见原因。这些疾病的有害临床结果有一个公认的遗传成分，但只有少数血小板基因变异与这些疾病有关。本申请的目的是鉴定负责血小板反应性的基因和遗传变异。我们的初步数据表明，血小板反应性是遗传和可重复的。我们发现，人类血小板聚集反应次最大肾上腺素刺激的双峰分布与显着不同的和非重叠的反应。我们选择了一组无关的欧洲裔美国人和非洲裔美国人的受试者，他们的血小板表现出极端的血小板反应性。全基因组关联研究是鉴定这一复杂生理系统的限速蛋白（基因）的有力方法。在目标1中，我们将使用Illumina HumanHap 550 BeadChip对我们具有高反应性和低反应性血小板的受试者的整个基因组中> 550，000个tagSNP进行基因分型。进行质量控制后，将对基因型和单体型数据进行分析。假发现率将用于选择假阳性率小于0.5的一组SNP。为了增强我们的候选人名单，包括新的基因和基因组扫描平台中没有得到很好的代表，在目标2中，我们将进行微阵列表达分析的mRNA血小板从一个子集的欧洲裔美国人和非洲裔美国人的极端血小板反应。在目标3中，将对目标1中鉴定的基因座和目标2中的基因进行定位，以获得具有致病遗传变异的更强LD中的SNP。在目标4中，我们将使用目标3中确定的SNP目标数量（约300-350）对约翰霍普金斯大学GeneSTAR队列中的所有受试者进行重复研究。这些研究的成功完成将通过发现负责血小板功能的新基因，对血小板生理学和关键信号通路产生新的见解。在这些基因中鉴定的变异体预期是改变血栓形成、出血和潜在的抗血小板药物的作用的因素。我们使用数量性状的极端的新方法可能对其他研究具有经济价值。

DESCRIPTION (provided by applicant): Platelet thrombi in coronary, cerebral and peripheral arteries are the most common cause of global morbidity and mortality. There is a well-established genetic component to the deleterious clinical outcomes of these disorders, but only a small number of platelet gene variations have been associated with these disorders. The goals of this application are to identify the genes and genetic variations responsible for platelet reactivity. Our preliminary data demonstrates that platelet reactivity is both heritable and reproducible. We find that the human platelet aggregation response to submaximal epinephrine stimulation is represented by a bimodal distribution with dramatically different and non-overlapping responses. We have selected groups of unrelated European American and African American subjects whose platelets demonstrate the extremes of platelet responsiveness. Genome wide association studies are powerful approaches for identifying rate- limiting proteins (genes) for this complex physiologic system. In Aim 1 we will genotype >550,000 tagSNPs throughout the genome of our subjects with hyper- and hyporeactive platelets using the Illumina HumanHap550 BeadChip. After performing quality control, analyses will be carried out on genotype and haplotype data. The False Discovery Rate will be used to select a group of SNPs with a false positive rate less than 0.5. To enhance our list of candidates to include novel genes and genes not well-represented in the genome scan platform, in Aim 2 we will perform microarray expression analyses with mRNA from platelets from a subset of European-Americans and African-Americans with extremes of platelet reactivity. In Aim 3 the loci identified in Aim 1 and the genes from Aim 2 will be mapped to obtain SNPs in stronger LD with the causative genetic variant. In Aim 4 we will use the targeted number of SNPs identified in Aim 3 (~300-350) to perform a replication study on all subjects in the Johns Hopkins University GeneSTAR cohort. The successful completion of these studies will result in new insights into platelet physiology and crucial signaling pathways via the discovery of novel genes responsible for platelet function. The variants identified in these genes are expected to be factors modifying thrombosis, hemorrhage and potentially the effects of anti-platelet agents. Our novel approach of using the extremes of a quantitative trait may prove economically valuable for other studies.